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Common host proteins required for replication organelle function across coronaviruses

冠状病毒复制细胞器功能所需的常见宿主蛋白

基本信息

批准号：
BB/T014571/1
负责人：
Helena Maier
金额：
$ 47.36万
依托单位：
The Pirbright Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT014571%2F1
关键词：
Common host proteins required replication

项目摘要

Coronaviruses are an important group of pathogens that infect both humans and livestock animals. Human coronaviruses mainly cause common cold-type illnesses and are responsible for approximately 10% of hospitalizations due to respiratory infections. In addition, an estimated 34 million working days were lost as a result of coughs and colds in 2016 meaning coronaviruses contribute to a major source of lost productivity. Coronaviruses are also responsible for economically important livestock diseases. The UK poultry industry contributes £3.4 billion annually to the economy and the most economically damaging infectious disease is caused by the coronavirus infectious bronchitis virus, with an estimated £23 million lost per year due to the disease. In pigs, an outbreak of another coronavirus, porcine epidemic diarrhoea virus, in the USA in 2013-2014 is estimated to have resulted in the death of 8 million pigs and is associated with estimated losses of $900 million - $1.8 billion across the whole economy. Finally, coronaviruses are able to jump between species resulting in new diseases, which are often highly pathogenic. This has happened twice since 2003 resulting in the emergence of SARS- and MERS-coronaviruses into the human population. There are currently no antiviral treatments available for coronaviruses and livestock industries require more effective vaccines that protect against multiple strains of virus. In order to develop new approaches to tackle coronaviruses, in particular ways to treat or prevent future, as yet unknown emerging coronaviruses, it is important to understand commonalities in how all coronaviruses behave and interact with their host cells.The synthesis of viral RNA is one stage of the coronavirus life cycle that is highly conserved and is critical for the propagation of new virus particles. This is required to direct the production of viral proteins that make up new particles and to produce copies of the viral genome to be packaged into new particles. Coronavirus RNA synthesis takes place at specialized sites called replication organelles (ROs). Our findings have shown that the appearance of ROs is conserved across all coronaviruses. However, little is known about how ROs form and which viral and cellular proteins are required. We propose that due to their central role in virus replication, and the fact that their appearance is highly conserved, all coronaviruses will hijack or use the same core set of host proteins to allow optimal RO assembly and function. An understanding of which cellular proteins all coronaviruses need to complete this critical stage of virus replication will underpin the development of universal anti-coronaviral drugs, development of vaccine viruses and even resistant livestock animals. In this project, we aim to identify and compare the viral and cellular proteins that are present in the ROs of a panel of five coronaviruses to identify the core set of host proteins required for this critical step of the coronavirus life cycle.

冠状病毒是一组重要的病原体，感染人类和家畜动物。人类冠状病毒主要引起常见的感冒型疾病，约占因呼吸道感染住院的10%。此外，2016年估计有3400万个工作日因咳嗽和感冒而损失，这意味着冠状病毒是生产力损失的主要来源。冠状病毒也是经济上重要的牲畜疾病的原因。英国家禽业每年为经济贡献34亿英镑，最具经济破坏性的传染病是由冠状病毒传染性支气管炎病毒引起的，估计每年因该疾病损失2300万英镑。在猪方面，2013-2014年美国爆发的另一种冠状病毒猪流行性腹泻病毒估计已导致800万头猪死亡，并在整个经济中造成估计9亿至18亿美元的损失。最后，冠状病毒能够在物种之间跳跃，导致新的疾病，这些疾病通常是高致病性的。自2003年以来，这种情况发生了两次，导致SARS和MERS冠状病毒进入人群。目前还没有针对冠状病毒的抗病毒治疗方法，畜牧业需要更有效的疫苗来抵御多种病毒株。为了开发新的方法来对付冠状病毒，特别是治疗或预防未来新出现的冠状病毒的方法，重要的是要了解所有冠状病毒如何表现及其与宿主细胞相互作用的共性。病毒RNA的合成是冠状病毒生命周期中高度保守的一个阶段，对于新病毒颗粒的繁殖至关重要。这需要指导病毒蛋白质的产生，这些蛋白质构成新的颗粒，并产生病毒基因组的拷贝以包装成新的颗粒。冠状病毒RNA合成发生在称为复制细胞器（RO）的专门位点。我们的研究结果表明，RO的外观在所有冠状病毒中都是保守的。然而，人们对RO如何形成以及需要哪些病毒和细胞蛋白知之甚少。我们提出，由于它们在病毒复制中的核心作用，以及它们的外观高度保守的事实，所有冠状病毒都将劫持或使用相同的宿主蛋白核心集，以实现最佳的RO组装和功能。了解所有冠状病毒需要哪些细胞蛋白来完成病毒复制的这一关键阶段，将为通用抗冠状病毒药物的开发、疫苗病毒的开发甚至耐药性家畜动物的开发奠定基础。在这个项目中，我们的目标是识别和比较存在于一组五种冠状病毒的RO中的病毒和细胞蛋白，以识别冠状病毒生命周期这一关键步骤所需的宿主蛋白的核心组。